The central aim of this proposal is to explore the anti-Staphylococcus aureus (S. aureus) activity of endogenous oleic acid (OA), a monounsaturated omega-9 free fatty acid (FFA) naturally existed in humans. The S. aureus bacteria, in particular, methicillin-resistant S. aureus (MRSA), are pathogenic and have a number of virulence factors that enable them to result in disease. They are transmissible and important causes of nosocomial infections worldwide. An MRSA outbreak can occur when one strain is transmitted to other patients or through close contacts of infected persons in the community. Our preliminary results indicated that OA is a biological molecule with bifunctionality: killing MRSA bacteria and enhancing host innate immunity. Here we propose three Specific Aims to (a) investigate the role of endogenous FFA in bacterial killing and host responses to FFA exposures;and (b) develop an FFA-derived new therapeutic against S. aureus/MRSA skin infections. Three Specific Aims are to (1) Examine the S. aureus strain selectivity of FFAs and investigate the anti-Staphylococcal activity of endogenous FFAs using FFAs-deficient mice;(2) Engineer a Nano-liposome-based FFA (Nano- LipoFFA) specifically targeting S. aureus and explore the bactericidal mechanism of Nano-LipoFFA via physicochemical analysis;and (3) Evaluate the potency of targeted Nano-LipoFFA against S. aureus skin infections and assess the host response to targeted Nano-LipoFFA. To carry out the proposed research, we have formed a solid research team consisting of two bacteriologists (Dr. Chun-Ming Huang, PI;Dr. Richard Gallo, co-investigator), a S. aureus expert (Dr. Victor Nizet, consultant), two nanotechnology engineers (Dr. Mirianas Chachisvilis, co-investigator and Dr. Liangfang Zhang, consultant), and a lipid biologist (Dr. Alan F. Hofmann, consultant). When successful, the results from this proposal will have broad impacts because (a) uncovering the role of endogenous free fatty acids in innate immunity will open a new area of research on host-pathogen interaction;(b) this work may provide a brand new approach to treat MRSA and S. aureus related infections, thereby benefiting the entire community of patients with MRSA infections consisting of over 126,000 patients per year in US;and (c) a similar strategy may potentially be used to treat various infections or diseases caused by other bacteria, thereby benefiting a larger patient community. PUBLIC HEALTH RELEVANCE: S. aureus infection on skin and soft tissue comprises more than 75% of MRSA disease. Treatment of S. aureus/MRSA skin infection using an endogenous oleic acid will be in compliance with evolutionary medicine since the endogenous compound causes a lower risk of developing new drug-resistant S. aureus strains and may have less side effects to patients.